Mucosal delivery of anti-inflammatory IL-1Ra by sporulating recombinant bacteria

BMC Biotechnology

Aldo Tagliabue¹  Diana Boraschi⁴  Paolo Ruggiero²  Paola Bossù⁵  Stefano Porzio³ 

[1]on leave to the International Vaccine Institute, SNU Research Park, San 4–8 Bongcheon-7 dong, Kwanak-gu, Seoul 151-818, Korea

[2]IRIS Research Center, Chiron Srl, Via Fiorentina 1, I-53100 Siena, Italy

[3]Inpharzam Ricerche SA, Zambon Group, Via ai Söi, CH-6807 Taverne, Switzerland

[4]Institute of Biomedical Technologies, CNR, Via G. Moruzzi 1, I-56124 Pisa, Italy

[5]Lab. Experimental Neuro-Psychobiology, Clinical and Behavioral Neurology, IRCCS Fondazione S. Lucia, Via Ardeatina 306, I-00179 Roma, Italy

Others  :  1154476
DOI  :  10.1186/1472-6750-4-27

 received in 2004-07-06, accepted in 2004-10-30,  发布年份 2004

【 摘 要 】

Background

Mucosal delivery of therapeutic protein drugs or vaccines is actively investigated, in order to improve bioavailability and avoid side effects associated with systemic administration. Orally administered bacteria, engineered to produce anti-inflammatory cytokines (IL-10, IL-1Ra), have shown localised ameliorating effects in inflammatory gastro-intestinal conditions. However, the possible systemic effects of mucosally delivered recombinant bacteria have not been investigated.

Results

B. subtilis was engineered to produce the mature human IL-1 receptor antagonist (IL-1Ra). When recombinant B. subtilis was instilled in the distal colon of rats or rabbits, human IL-1Ra was found both in the intestinal lavage and in the serum of treated animals. The IL-1Ra protein in serum was intact and biologically active. IL-1-induced fever, neutrophilia, hypoglycemia and hypoferremia were inhibited in a dose-dependent fashion by intra-colon administration of IL-1Ra-producing B. subtilis. In the mouse, intra-peritoneal treatment with recombinant B. subtilis could inhibit endotoxin-induced shock and death. Instillation in the rabbit colon of another recombinant B. subtilis strain, which releases bioactive human recombinant IL-1β upon autolysis, could induce fever and eventually death, similarly to parenteral administration of high doses of IL-1β.

Conclusions

A novel system of controlled release of pharmacologically active proteins is described, which exploits bacterial autolysis in a non-permissive environment. Mucosal administration of recombinant B. subtilis causes the release of cytoplasmic recombinant proteins, which can then be found in serum and exert their biological activity in vivo systemically.

【 授权许可】

   
2004 Porzio et al; licensee BioMed Central Ltd.

【 图 表 】

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